Journal of Pathology and Translational Medicine

Case Study

Metastatic choroidal melanoma in the breast: a case report and review of the literature: Loay Abudalu, Vinisha Malhotra, Nabila Nasir, Sami Titi; J Pathol Transl Med. 2023;57(4):238-241. Published online July 11, 2023; DOI: https://doi.org/10.4132/jptm.2023.06.07

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Abstract PDF: The breast is an unusual site for metastases, accounting for less than 2% of malignant breast lesions but include those from malignant melanomas, carcinomas, sarcomas, and lymphomas from various organs. We diagnosed a very rare case of metastatic choroidal melanoma for a 67-year-old female who presented with a right breast lump and who had been previously diagnosed with choroidal melanoma-monosomy 3 in 2017. To the best of our knowledge, only five such cases have been published so far, with one in a male patient.

Original Articles

Fatty acid synthetase expression in triple-negative breast cancer: Jin Hee Park, Hye Seung Han, So Dug Lim, Wook Youn Kim, Kyoung Sik Park, Young Bum Yoo, Seung Eun Lee, Wan-Seop Kim; J Pathol Transl Med. 2022;56(2):73-80. Published online January 21, 2022; DOI: https://doi.org/10.4132/jptm.2021.10.27

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Background
Triple-negative breast cancer (TNBC) has a relatively poor prognosis. Research has identified potential metabolic targets, including fatty acid metabolism, in TNBC. The absence of effective target therapies for TNBC led to exploration of the role of fatty acid synthetase (FASN) as a potential target for TNBC therapy. Here, we analyzed the expression of FASN, a representative lipid metabolism–related protein, and investigated the association between FASN expression and Ki-67 and the programmed death ligand 1 (PD-L1) biomarkers in TNBC.
Methods
Immunohistochemical expression of FASN was analyzed in 166 patients with TNBC. For analytical purposes, patients with 0–1+ FASN staining were grouped as low-grade FASN and patients with 2–3+ FASN staining as high-grade FASN.
Results
FASN expression was observed in 47.1% of TNBC patients. Low and high expression of FASN was identified in 75.9% and 24.1%, respectively, and no statistically significant difference was found in T category, N category, American Joint Committee on Cancer stage, or recurrence rate between the low and high-FASN expression groups. Ki-67 proliferation level was significantly different between the low and high-FASN expression groups. FASN expression was significantly related to Ki-67 as the level increased. There was no significant difference in PD-L1 positivity between the low- and high-FASN expression groups.
Conclusions
We identified FASN expression in 166 TNBC patients. The Ki-67 proliferation index was positively correlated with FASN level, indicating higher proliferation activity as FASN increases. However, there was no statistical association with PD-L1 SP142, the currently FDA-approved assay, or FASN expression level.

Citations

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NFYA promotes malignant behavior of triple-negative breast cancer in mice through the regulation of lipid metabolism
Nobuhiro Okada, Chihiro Ueki, Masahiro Shimazaki, Goki Tsujimoto, Susumu Kohno, Hayato Muranaka, Kiyotsugu Yoshikawa, Chiaki Takahashi
Communications Biology.2023;[Epub] CrossRef
Role of EGFR and FASN in breast cancer progression
Suchi Chaturvedi, Mainak Biswas, Sushabhan Sadhukhan, Avinash Sonawane
Journal of Cell Communication and Signaling.2023; 17(4): 1249. CrossRef
Bioinformatics Method Was Used to Analyze the Highly Expressed Gene FAM83A of Breast Cancer in Young Women
Yongzhe Tang, Hao Wang, Qi He, Yuanyuan Chen, Jie Wang, Fahd Abd Algalil
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NCAPH promotes proliferation as well as motility of breast cancer cells by activating the PI3K/AKT pathway
Ting Zhang, Peng Li, Wanying Guo, Qipeng Liu, Weiqiang Qiao, Miao Deng
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Potential of AKT2 expression as a predictor of lymph-node metastasis in invasive breast carcinoma of no special type: Primariadewi Rustamadji, Elvan Wiyarta, Kristina Anna Bethania, Kusmardi Kusmardi; J Pathol Transl Med. 2021;55(4):271-278. Published online June 14, 2021; DOI: https://doi.org/10.4132/jptm.2021.04.26

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Abstract PDF

Background
Invasive breast carcinoma of no special type (IBC-NST) is the most common type of breast cancer and mainly causes regional lymph-node metastasis (LNM). We investigated the potential for AKT2 expression as a predictive biomarker for LNM in IBC-NST.
Methods
Forty-eight paraffin blocks containing IBC-NST primary tumors were divided into two groups based on presence or absence of LNM. Age, tumor grade, tumor size, lymphovascular invasion (LVI), and AKT expression were assessed. AKT2 expression was assessed based on immunohistochemical staining, while other data were collected from archives.
Results
Multiple logistic regression results showed that AKT2 expression and LVI were significantly associated with LNM (odds ratio [OR], 5.32; 95% confidence interval [CI], 1.42 to 19.93 and OR, 4.46; 95% CI, 1.17 to 16.97, respectively). AKT2 expression was able to discriminate against LNM (area under the receiver operating characteristic, 0.799 ± 0.063; 95% CI, 0.676 to 0.921) at an H-score cutoff of 104.62 (83.3% sensitivity, 62.5% specificity).
Conclusions
AKT2 expression has potential as a predictor of LNM in IBC-NST. The H-score cutoff for AKT2 expression can be used as a classification guide in future studies.

Citations

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Exploring the Expression of Survivin on Neoadjuvant Chemotherapy in Invasive Breast Carcinoma
Primariadewi Rustamadji, Elvan Wiyarta, Ineke Anggreani
Open Access Macedonian Journal of Medical Sciences.2022; 10(B): 1440. CrossRef
Effect of Omega-3-Rich Fish Oil on TNF-  Expression in Mice's Colonic Tissue Induced with Azoxymethane (AOM) and Dextran Sodium Sulphate (DSS)
Elvan Wiyarta, Kusmardi Kusmardi, Yurnadi Hanafi Midoen
Research Journal of Pharmacy and Technology.2022; : 3179. CrossRef
The potential of lunasin extract for the prevention of breast cancer progression by upregulating E-Cadherin and inhibiting ICAM-1
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CD44 Variant Exon 6 Isoform Expression as a Potential Predictor of Lymph Node Metastasis in Invasive Breast Carcinoma of No Special Type
Primariadewi Rustamadji, Elvan Wiyarta, Kristina A. Bethania, Rakesh Sathish Nair
International Journal of Breast Cancer.2021; 2021: 1. CrossRef

Review

Standardized pathology report for breast cancer: Soo Youn Cho, So Yeon Park, Young Kyung Bae, Jee Yeon Kim, Eun Kyung Kim, Woo Gyeong Kim, Youngmee Kwon, Ahwon Lee, Hee Jin Lee, Ji Shin Lee, Jee Young Park, Gyungyub Gong, Hye Kyoung Yoon; J Pathol Transl Med. 2021;55(1):1-15. Published online January 11, 2021; DOI: https://doi.org/10.4132/jptm.2020.11.20

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Abstract PDF Supplementary Material

Given the recent advances in management and understanding of breast cancer, a standardized pathology report reflecting these changes is critical. To meet this need, the Breast Pathology Study Group of the Korean Society of Pathologists has developed a standardized pathology reporting format for breast cancer, consisting of ‘standard data elements,’ ‘conditional data elements,’ and a biomarker report form. The ‘standard data elements’ consist of the basic pathologic features used for prognostication, while other factors related to prognosis or diagnosis are described in the ‘conditional data elements.’ In addition to standard data elements, all recommended issues are also presented. We expect that this standardized pathology report for breast cancer will improve diagnostic concordance and communication between pathologists and clinicians, as well as between pathologists inter-institutionally.

Citations

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Residual pure intralymphatic carcinoma component only (lymphovascular tumor emboli without invasive carcinoma) after neoadjuvant chemotherapy is associated with poor outcome: Not pathologic complete response
Hyunwoo Lee, Yunjeong Jang, Yoon Ah Cho, Eun Yoon Cho
Human Pathology.2024; 145: 1. CrossRef
Sentinel lymph node biopsy in patients with ductal carcinomain situ: systematic review and meta-analysis
Matthew G. Davey, Colm O’Flaherty, Eoin F. Cleere, Aoife Nohilly, James Phelan, Evan Ronane, Aoife J. Lowery, Michael J. Kerin
BJS Open.2022;[Epub] CrossRef

Original Article

Automated immunohistochemical assessment ability to evaluate estrogen and progesterone receptor status compared with quantitative reverse transcription-polymerase chain reaction in breast carcinoma patients: Taesung Jeon, Aeree Kim, Chungyeul Kim; J Pathol Transl Med. 2021;55(1):33-42. Published online December 3, 2020; DOI: https://doi.org/10.4132/jptm.2020.09.29

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Abstract PDF

Background
This study aimed to investigate the capability of an automated immunohistochemical (IHC) evaluation of hormonal receptor status in breast cancer patients compared to a well-validated quantitative reverse transcription–polymerase chain reaction (RT-qPCR) method.
Methods
This study included 93 invasive breast carcinoma cases that had both standard IHC assay and Oncotype Dx assay results. The same paraffin blocks on which Oncotype Dx assay had been performed were selected. Estrogen receptor (ER) and progesterone receptor (PR) receptor status were evaluated through IHC stains using SP1 monoclonal antibody for ER, and 1E2 monoclonal antibody for PR. All ER and PR immunostained slides were scanned, and invasive tumor areas were marked. Using the QuantCenter image analyzer provided by 3DHISTECH, IHC staining of hormone receptors was measured and converted to histochemical scores (H scores). Pearson correlation coefficients were calculated between Oncotype Dx hormone receptor scores and H scores, and between Oncotype Dx scores and Allred scores.
Results
H scores measured by an automated imaging system showed high concordance with RT-qPCR scores. ER concordance was 98.9% (92/93), and PR concordance was 91.4% (85/93). The correlation magnitude between automated H scores and RT-qPCR scores was high and comparable to those of Allred scores (for ER, 0.51 vs. 0.37 [p=.121], for PR, 0.70 vs. 0.72 [p=.39]).
Conclusions
Automated H scores showed a high concordance with quantitative mRNA expression levels measured by RT-qPCR.

Citations

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Gelan Ayana, Eonjin Lee, Se-woon Choe
The American Journal of Pathology.2024; 194(3): 402. CrossRef
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Joshua J X Li, Gary M Tse
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Rohit Bhargava, David J. Dabbs
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Dose-Dependent Relationship between Protection of Thioacetamide-Induced Acute Liver Injury and Hyperammonemia and Concentration of Lactobacillus salivarius Li01 in Mice
Pengcheng Lou, Yangfan Shen, Aoxiang Zhuge, Longxian Lv, Xueling Zhu, Yin Yuan, Liya Yang, Kaicen Wang, Bo Li, Lanjuan Li, Joanna B. Goldberg
Microbiology Spectrum.2021;[Epub] CrossRef

Reviews

Imaging features of breast cancer molecular subtypes: state of the art: Nariya Cho; J Pathol Transl Med. 2021;55(1):16-25. Published online November 9, 2020; DOI: https://doi.org/10.4132/jptm.2020.09.03

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Abstract PDF

Characterization of breast cancer molecular subtypes has been the standard of care for breast cancer management. We aimed to provide a review of imaging features of breast cancer molecular subtypes for the field of precision medicine. We also provide an update on the recent progress in precision medicine for breast cancer, implications for imaging, and recent observations in longitudinal functional imaging with radiomics.

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Association of clinicopathologic and molecular factors with the occurrence of positive margins in breast cancer
Anupama Praveen Kumar, Diego Vicente, Jianfang Liu, Praveen-Kumar Raj-Kumar, Brenda Deyarmin, Xiaoying Lin, Craig D. Shriver, Hai Hu
Breast Cancer Research and Treatment.2024; 204(1): 15. CrossRef
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Aydin Demircioğlu
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Treated Primary Cutaneous Malignant Melanoma With Later Metastasis Found in Clinical Presentation of Left Axilla Lymphadenopathy: A Case Report
Brigitte L Cochran, Sara Eliseo, Austin Vaughn, Tamryn L Van Der Horn, Enzo Ferrara, Jamie Edwards
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Histogram analysis of multi-model high-resolution diffusion-weighted MRI in breast cancer: correlations with molecular prognostic factors and subtypes
Yanjin Qin, Feng Wu, Qilan Hu, Litong He, Min Huo, Caili Tang, Jingru Yi, Huiting Zhang, Ting Yin, Tao Ai
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Kai Huang, James W. Jakub, Sarah A. McLaughlin
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Circulating non-coding RNAs as a diagnostic and management biomarker for breast cancer: current insights
Hamed Hosseinalizadeh, Mehrdad Mahmoodpour, Ammar Ebrahimi
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MRI as a biomarker for breast cancer diagnosis and prognosis
Francesca Galati, Veronica Rizzo, Rubina Manuela Trimboli, Endi Kripa, Roberto Maroncelli, Federica Pediconi
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Multiparametric MRI Features of Breast Cancer Molecular Subtypes
Madalina Szep, Roxana Pintican, Bianca Boca, Andra Perja, Magdalena Duma, Diana Feier, Bogdan Fetica, Dan Eniu, Sorin Marian Dudea, Angelica Chiorean
Medicina.2022; 58(12): 1716. CrossRef
Circulating tumor cells as prognostic biomarkers in breast cancer: current status and future prospects
Evagelia Chantzara, Nikolaos Xenidis, Galatea Kallergi, Vassilis Georgoulias, Athanasios Kotsakis
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Clinicopathological characteristics of BRCA-associated breast cancer in Asian patients: Eun-Kyu Kim, So Yeon Park, Sung-Won Kim; J Pathol Transl Med. 2020;54(4):265-275. Published online May 14, 2020; DOI: https://doi.org/10.4132/jptm.2020.04.07

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Abstract PDF

BRCA1/2 germline mutations account for the majority of hereditary breast cancers. Since the identification of the BRCA genes, several attempts have been made to define the clinicopathological characteristics of BRCA-associated breast cancer in comparison with sporadic breast cancer. Asians constitute 60% of the world population, and although the incidence of breast cancer in Asia remains low compared to the West, breast cancer is the most prevalent female cancer in the region. The epidemiological aspects of breast cancer are different between Asians and Caucasians. Asian patients present with breast cancer at a younger age than Western patients. The contributions of BRCA1/2 mutations to breast cancer incidence are expected to differ between Asians and Caucasians, and the different genetic backgrounds among races are likely to influence the breast cancer phenotypes. However, most large-scale studies on the clinicopathological characteristics of BRCA-associated breast cancer have been on Western patients, while studies on Asian populations were small and sporadic. In this review, we provide an overview of the clinical and pathological characteristics of BRCA-associated breast cancer, incorporating findings on Asian patients.

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Characteristics of breast cancer patients tested for germline BRCA1/2 mutations by next‐generation sequencing in Ramathibodi Hospital, Mahidol University
Songporn Oranratnachai, Watchalawalee Yamkaew, Atchara Tunteeratum, Thongchai Sukarayothin, Nareenart Iemwimangsa, Ravat Panvichien
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Mutations of TP53 and genes related to homologous recombination repair in breast cancer with germline BRCA1/2 mutations
Jinyong Kim, Kyeonghun Jeong, Hyeji Jun, Kwangsoo Kim, Jeong Mo Bae, Myung Geun Song, Hanbaek Yi, Songyi Park, Go-un Woo, Dae-Won Lee, Tae-Yong Kim, Kyung-Hun Lee, Seock-Ah Im
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BRCA 1–2 Incidence in Synchronous and Metachronous Breast Cancer: a Tertiary Center Study
Ahmet Dağ, Bilal Arslan, Erkan Güler, Serdar Mermer
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Habitat Analysis of Breast Cancer-Enhanced MRI Reflects BRCA1 Mutation Determined by Immunohistochemistry
Tianming Du, Haidong Zhao, Chen Li
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Guoding Huang, Hongquan Lu, Qizhu Chen, Xinting Huang
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The clinical and diagnostic characteristics of BRCA-associated breast cancer
M.A. Golotyuk, A.A. Berezhnoy, N.V. Kazantseva, A.V. Dorofeev, S.A. Shevchenko, I.V. Borzunov, N.I. Rozhkova
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Original Articles

Clinicopathologic characteristics of HER2-positive pure mucinous carcinoma of the breast: Yunjeong Jang, Hera Jung, Han-Na Kim, Youjeong Seo, Emad Alsharif, Seok Jin Nam, Seok Won Kim, Jeong Eon Lee, Yeon Hee Park, Eun Yoon Cho, Soo Youn Cho; J Pathol Transl Med. 2020;54(1):95-102. Published online November 13, 2019; DOI: https://doi.org/10.4132/jptm.2019.10.24

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Abstract PDF

Background
Pure mucinous carcinoma (PMC) is a rare type of breast cancer, estimated to represent 2% of invasive breast cancer. PMC is typically positive for estrogen receptors (ER) and progesterone receptors (PR) and negative for human epidermal growth factor receptor 2 (HER2). The clinicopathologic characteristics of HER2-positive PMC have not been investigated.
Methods
Pathology archives were searched for PMC diagnosed from January 1999 to April 2018. Clinicopathologic data and microscopic findings were reviewed and compared between HER2-positive PMC and HER2-negative PMC. We also analyzed the differences in disease-free survival (DFS) and overall survival according to clinicopathologic parameters including HER2 status in overall PMC cases.
Results
There were 21 HER2-positive cases (4.8%) in 438 PMCs. The average tumor size of HER2-positive PMC was 32.21 mm (± 26.55). Lymph node metastasis was present in seven cases. Compared to HER2-negative PMC, HER2-positive PMC presented with a more advanced T category (p < .001), more frequent lymph node metastasis (p = .009), and a higher nuclear and histologic grade (p < .001). Microscopically, signet ring cells were frequently observed in HER2-positive PMC (p < .001), whereas a micropapillary pattern was more frequent in HER2-negative PMC (p = .012). HER2-positive PMC was more frequently negative for ER (33.3% vs. 1.2%) and PR (28.6% vs. 7.2%) than HER2-negative PMC and showed a high Ki-67 labeling index. During follow-up, distant metastasis and recurrence developed in three HER2-positive PMC patients. Multivariate analysis revealed that only HER2-positivity and lymph node status were significantly associated with DFS.
Conclusions
Our results suggest that HER2-positive PMC is a more aggressive subgroup of PMC. HER2 positivity should be considered for adequate management of PMC.

Citations

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Pure Mucinous Carcinoma of the Breast: Radiologic-Pathologic Correlation
Cherie M Kuzmiak, Benjamin C Calhoun
Journal of Breast Imaging.2023;[Epub] CrossRef
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Elahe Abdollahi, Hossein Mozdarani, Behrooz Z. Alizadeh
Breast Cancer.2023; 30(5): 714. CrossRef
On Ultrasonographic Features of Mucinous Carcinoma with Micropapillary Pattern
Wei-Sen Yang, Yang Li, Ya Gao
Breast Cancer: Targets and Therapy.2023; Volume 15: 473. CrossRef
Comprehensive Immunohistochemical Analysis of Mesonephric Marker Expression in Low-grade Endometrial Endometrioid Carcinoma
Yurimi Lee, Sangjoon Choi, Hyun-Soo Kim
International Journal of Gynecological Pathology.2023;[Epub] CrossRef
Spectrum of Mucin-containing Lesions of the Breast: Multimodality Imaging Review with Pathologic Correlation
Janice N. Thai, Melinda F. Lerwill, Shinn-Huey S. Chou
RadioGraphics.2023;[Epub] CrossRef
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Hyun Hee Koh, Eunhyang Park, Hyun-Soo Kim
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Yurimi Lee, Kiyong Na, Ha Young Woo, Hyun-Soo Kim
Diagnostics.2022; 12(5): 1102. CrossRef
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Ivana Mijatov, Aleksandra Fejsa Levakov, Aleksandar Spasić, Jelena Nikolić, Saša Mijatov
Medicine.2022; 101(38): e30732. CrossRef
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Jihee Sohn, Yurimi Lee, Hyun-Soo Kim
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Sangjoon Choi, Yoon Yang Jung, Hyun-Soo Kim
Diagnostics.2021; 11(4): 717. CrossRef
HER2 positive mucinous carcinoma of breast with micropapillary features: Report of a case and review of literature
Dinesh Chandra Doval, Rupal Tripathi, Sunil Pasricha, Pankaj Goyal, Chaturbhuj Agrawal, Anurag Mehta
Human Pathology: Case Reports.2021; 25: 200531. CrossRef
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A.M. González Aranda, E. Martínez Gómez, A. Santana Costa, F. Arnanz Velasco, M.H. González de Diego, A. Zapico Goñi
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Sujin Park, Go Eun Bae, Jiyoung Kim, Hyun-Soo Kim
Diagnostics.2021; 11(8): 1450. CrossRef
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Hyunjin Kim, Kiyong Na, Go Eun Bae, Hyun-Soo Kim
Diagnostics.2021; 11(11): 2042. CrossRef

Analysis of the molecular subtypes of preoperative core needle biopsy and surgical specimens in invasive breast cancer: Ye Sul Jeong, Jun Kang, Jieun Lee, Tae-Kyung Yoo, Sung Hun Kim, Ahwon Lee; J Pathol Transl Med. 2020;54(1):87-94. Published online November 13, 2019; DOI: https://doi.org/10.4132/jptm.2019.10.14

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Abstract PDF

Background
Accurate molecular classification of breast core needle biopsy (CNB) tissue is important for determining neoadjuvant systemic therapies for invasive breast cancer. The researchers aimed to evaluate the concordance rate (CR) of molecular subtypes between CNBs and surgical specimens.
Methods
This study was conducted with invasive breast cancer patients who underwent surgery after CNB at Seoul St. Mary’s Hospital between December 2014 and December 2017. Estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and Ki67 were analyzed using immunohistochemistry. ER and PR were evaluated by Allred score (0–8). HER2 was graded from 0 to +3, and all 2+ cases were reflex tested with silver in situ hybridization. The labeling index of Ki67 was counted by either manual scoring or digital image analysis. Molecular subtypes were classified using the above surrogate markers.
Results
In total, 629 patients were evaluated. The CRs of ER, PR, HER2, and Ki67 were 96.5% (kappa, 0.883; p<.001), 93.0% (kappa, 0.824; p<.001), 99.7% (kappa, 0.988; p<.001), and 78.7% (kappa, 0.577; p<.001), respectively. Digital image analysis of Ki67 in CNB showed better concordance with Ki67 in surgical specimens (CR, 82.3%; kappa, 0.639 for digital image analysis vs. CR, 76.2%; kappa, 0.534 for manual counting). The CRs of luminal A, luminal B, HER2, and triple negative types were 89.0%, 70.0%, 82.9%, and 77.2%, respectively.
Conclusions
CNB was reasonably accurate for determining ER, PR, HER2, Ki67, and molecular subtypes. Using digital image analysis for Ki67 in CNB produced more accurate molecular classifications.

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Jahnavi Kalvala, Ruth M Parks, Andrew R Green, Kwok‐Leung Cheung
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İnvaziv Meme Kanserinde Preoperatif Kor İğne Biyopsi ile Postoperatif Cerrahi Spesmenler Arasında ER, PR, HER2 ve Ki67 Açısından Karşılaştırma
Pınar CELEPLİ, Pelin Seher ÖZTEKİN, Salih CELEPLİ, İrem BİGAT, Sema HÜCÜMENOĞLU
Akdeniz Medical Journal.2022; : 179. CrossRef
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Jessica A. Slostad, Nicole K. Yun, Aimee E. Schad, Surbhi Warrior, Louis F. Fogg, Ruta Rao
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Association between p53 Expression and Amount of Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer: Miseon Lee, In Ah Park, Sun-Hee Heo, Young-Ae Kim, Gyungyub Gong, Hee Jin Lee; J Pathol Transl Med. 2019;53(3):180-187. Published online March 11, 2019; DOI: https://doi.org/10.4132/jptm.2019.02.08

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Abstract PDF

Background
Most triple-negative breast cancers (TNBCs) have a high histologic grade, are associated with high endoplasmic stress, and possess a high frequency of TP53 mutations. TP53 missense mutations lead to the production of mutant p53 protein and usually show high levels of p53 protein expression. Tumor-infiltrating lymphocytes (TILs) accumulate as part of the anti-tumor immune response and have a strong prognostic and predictive significance in TNBC. We aimed to elucidate the association between p53 expression and the amount of TILs in TNBC.
Methods
In 678 TNBC patients, we evaluated TIL levels and expression of endoplasmic stress molecules. Immunohistochemical examination of p53 protein expression was categorized into three groups: no, low, and high expression.
Results
No, low, and high p53 expression was identified in 44.1% (n = 299), 20.1% (n = 136), and 35.8% (n = 243) of patients, respectively. Patients with high p53 expression showed high histologic grade (p < .001), high TIL levels (p = .009), and high expression of endoplasmic reticulum stress-associated molecules (p-eIF2a, p = .013; XBP1, p = .007), compared to patients with low p53 expression. There was no significant difference in disease-free (p = .406) or overall survival rates (p = .444) among the three p53 expression groups.
Conclusions
High p53 expression is associated with increased expression of endoplasmic reticulum stress molecules and TIL influx.

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Rupert Bartsch, Gabriel Rinnerthaler, Edgar Petru, Daniel Egle, Michael Gnant, Marija Balic, Thamer Sliwa, Christian Singer
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Uterine Malignant Mixed Müllerian Tumors Following Treatment with Selective Estrogen Receptor Modulators in Patients with Breast Cancer: A Report of 13 Cases and Their Clinicopathologic Characteristics: Byung-Kwan Jeong, Chang O. Sung, Kyu-Rae Kim; J Pathol Transl Med. 2019;53(1):31-39. Published online December 18, 2018; DOI: https://doi.org/10.4132/jptm.2018.11.16

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Abstract PDF

Background
Breast cancer treatment with selective estrogen receptor modulators (SERMs) increasesthe incidence of uterine malignant mixed Müllerian tumors (uMMMTs). We examine clinicopathologiccharacteristics and prognosis of SERM-associated uMMMTs (S-uMMMTs) and discusspossible pathogenetic mechanisms.
Methods
Among 28,104 patients with breast cancer, clinicopathologicfeatures and incidence of uMMMT were compared between patients who underwentSERM treatment and those who did not. Of 92 uMMMT cases that occurred during the same period,incidence, dose, and duration of SERM treatment, as well as overall survival rate, were comparedfor patients with breast cancer who underwent SERM treatment and those who did not (S-uMMMTvs NS-uMMMT) and for patients without breast cancer (de novo-uMMMT). Histopathologicalfindings and immunophenotypes for myogenin, desmin, p53, WT-1, estrogen receptor (ER) α, ERβ,progesterone receptor, and GATA-3 were compared between S-uMMMT and de novo-uMMMT.
Results
The incidence of S-uMMMT was significantly higher than that of NS-uMMMT (6.35-fold).All patients with SERM were postmenopausal and received daily 20–40 mg SERM. CumulativeSERM dose ranged from 21.9 to 73.0 g (mean, 46.0) over 39–192 months (mean, 107). Clinicopathologicfeatures, such as International Federation of Gynecology and Obstetrics stage andoverall survival, were not significantly different between patients with S-uMMMT and NS-uMMMTor between patients with S-uMMMT and de novo-uMMMT. All 11 S-uMMMT cases available forimmunostaining exhibited strong overexpression/null expression of p53 protein and significantlyincreased ERβ expression in carcinomatous and sarcomatous components.
Conclusions
SERMtherapy seemingly increases risk of S-uMMMT development; however, clinicopathologic featureswere similar in all uMMMTs from different backgrounds. p53 mutation and increased ERβ expressionmight be involved in the etiology of S-uMMMT.

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Tamoxifen/toremifene

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Loss of Human Leukocyte Antigen Class I Expression Is Associated with Poor Prognosis in Patients with Advanced Breast Cancer: Hong Sik Park, Uiju Cho, So Young Im, Chang Young Yoo, Ji Han Jung, Young Jin Suh, Hyun Joo Choi; J Pathol Transl Med. 2019;53(2):75-85. Published online November 14, 2018; DOI: https://doi.org/10.4132/jptm.2018.10.11

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Abstract PDF

Background
Human leukocyte antigen class I (HLA-I) molecules play important roles in regulating immune responses. Loss or reduction of HLA-I expression has been shown to be associated with prognosis in several cancers. Regulatory T-cells (Tregs) also play critical functions in immune response regulation. Evaluation of HLA-I expression status by the EMR8-5 antibody and its clinical impact in breast cancer have not been well studied, and its relationship with Tregs remains unclear.
Methods
We evaluated HLA-I expression and Treg infiltration by immunohistochemistry in 465 surgically resected breast cancer samples. We examined the correlation between HLA-I expression and Treg infiltration and clinicopathologic characteristics and survival analyses were performed.
Results
Total loss of HLA-I expression was found in 84 breast cancer samples (18.1%). Univariate survival analysis revealed that loss of HLA-I expression was significantly associated with worse disease-specific survival (DSS) (p = .029). HLA-I was not an independent prognostic factor in the entire patient group, but it was an adverse independent prognostic factor for DSS in patients with advanced disease (stage II–IV) (p = .031). Treg numbers were significantly higher in the intratumoral stroma of HLA-I–positive tumors than in HLA-I–negative tumors (median 6.3 cells/high power field vs 2.1 cells/high power field, p < .001). However, Tregs were not an independent prognostic factor in our cohort.
Conclusions
Our findings suggest that the loss of HLA-I expression is associated with poor prognosis in breast cancer patients, highlighting the role of HLA-I alterations in immune evasion mechanisms of breast cancer. HLA-I could be a promising marker that enables the application of more effective and precise immunotherapies for patients with advanced breast cancer.

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Comment on “Prognostic and Clinical Significance of Human Leukocyte Antigen Class I Expression in Breast Cancer: A Meta‑Analysis”
Wei Han, Li-zhou Shi, Yu-wei Zhang, Hao-nan Wang
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The Prognostic Impact of Synchronous Ipsilateral Multiple Breast Cancer: Survival Outcomes according to the Eighth American Joint Committee on Cancer Staging and Molecular Subtype: Jinah Chu, Hyunsik Bae, Youjeong Seo, Soo Youn Cho, Seok-Hyung Kim, Eun Yoon Cho; J Pathol Transl Med. 2018;52(6):396-403. Published online October 23, 2018; DOI: https://doi.org/10.4132/jptm.2018.10.03

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Abstract PDF

Background
In the current American Joint Committee on Cancer staging system of breast cancer, only tumor size determines T-category regardless of whether the tumor is single or multiple. This study evaluated if tumor multiplicity has prognostic value and can be used to subclassify breast cancer.
Methods
We included 5,758 patients with invasive breast cancer who underwent surgery at Samsung Medical Center, Seoul, Korea, from 1995 to 2012.
Results
Patients were divided into two groups according to multiplicity (single, n = 4,744; multiple, n = 1,014). Statistically significant differences in lymph node involvement and lymphatic invasion were found between the two groups (p < .001). Patients with multiple masses tended to have luminal A molecular subtype (p < .001). On Kaplan-Meier survival analysis, patients with multiple masses had significantly poorer disease-free survival (DFS) (p = .016). The prognostic significance of multiplicity was seen in patients with anatomic staging group I and prognostic staging group IA (p = .019 and p = .032, respectively). When targeting patients with T1-2 N0 M0, hormone receptor–positive, and human epidermal growth factor receptor 2 (HER2)–negative cancer, Kaplan-Meier survival analysis also revealed significantly reduced DFS with multiple cancer (p = .031). The multivariate analysis indicated that multiplicity was independently correlated with worse DFS (hazard ratio, 1.23; 95% confidence interval, 1.03 to 1.47; p = .025). The results of this study indicate that tumor multiplicity is frequently found in luminal A subtype, is associated with frequent lymph node metastasis, and is correlated with worse DFS.
Conclusions
Tumor multiplicity has prognostic value and could be used to subclassify invasive breast cancer at early stages. Adjuvant chemotherapy would be necessary for multiple masses of T1–2 N0 M0, hormone-receptor-positive, and HER2-negative cancer.

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Alexandre Boulenger, Yanwen Luo, Chenhui Zhang, Chenyang Zhao, Yuanjing Gao, Mengsu Xiao, Qingli Zhu, Jie Tang
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Noorsuzana Mohd Shariff, Nizuwan Azman, Rohayu Hami, Noor Mastura Mohd Mujar, Mohammad Farris Iman Leong Bin Abdullah
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High Cytoplasmic CXCR4 Expression Predicts Prolonged Survival in Triple-Negative Breast Cancer Patients Treated with Adjuvant Chemotherapy: Bobae Shim, Min‐Sun Jin, Ji Hye Moon, In Ae Park, Han Suk Ryu; J Pathol Transl Med. 2018;52(6):369-377. Published online October 1, 2018; DOI: https://doi.org/10.4132/jptm.2018.09.19

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Abstract PDF

Background
Chemokine receptor CXC chemokine receptor type 4 (CXCR4) and its ligand CXC motif chemokine 12 (CXCL12; stromal cell-derived factor-1) are implicated in tumor growth, metastasis, and tumor cell-microenvironment interaction. A number of studies have reported that increased CXCR4 expression is associated with worse prognosis in triple-negative breast cancer (TNBC), but its prognostic significance has not been studied in TNBC patients treated with adjuvant chemotherapy.
Methods
Two hundred eighty-three TNBC patients who received adjuvant chemotherapy were retrospectively analyzed. Tissue microarray was constructed from formalinfixed, paraffin-embedded tumor tissue and immunohistochemistry for CXCR4 and CXCL12 was performed. Expression of each marker was compared with clinicopathologic characteristics and outcome.
Results
High cytoplasmic CXCR4 expression was associated with younger age (p = .008), higher histologic grade (p = .007) and lower pathologic stage (p = .045), while high CXCL12 expression was related to larger tumor size (p = .045), positive lymph node metastasis (p = .005), and higher pathologic stage (p = .017). The patients with high cytoplasmic CXCR4 experienced lower distant recurrence (p = .006) and better recurrence-free survival (RFS) (log-rank p = .020) after adjuvant chemotherapy. Cytoplasmic CXCR4 expression remained an independent factor of distant recurrence (p = .019) and RFS (p = .038) after multivariate analysis.
Conclusions
High cytoplasmic CXCR4 expression was associated with lower distant recurrence and better RFS in TNBC patients treated with adjuvant chemotherapy. This is the first study to correlate high CXCR4 expression to better TNBC prognosis, and the underlying mechanism needs to be elucidated in further studies.

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Irina Chifu, Britta Heinze, Carmina T. Fuss, Katharina Lang, Matthias Kroiss, Stefan Kircher, Cristina L. Ronchi, Barbara Altieri, Andreas Schirbel, Martin Fassnacht, Stefanie Hahner
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Evaluation of Pathologic Complete Response in Breast Cancer Patients Treated with Neoadjuvant Chemotherapy: Experience in a Single Institution over a 10-Year Period: Misun Choi, Yeon Hee Park, Jin Seok Ahn, Young-Hyuck Im, Seok Jin Nam, Soo Youn Cho, Eun Yoon Cho; J Pathol Transl Med. 2017;51(1):69-78. Published online December 25, 2016; DOI: https://doi.org/10.4132/jptm.2016.10.05

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Background
Pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) has been associated with favorable clinical outcome in breast cancer patients. However, the possibility that the prognostic significance of pCR differs among various definitions has not been established. Methods: We retrospectively evaluated the pathologic response after NAC in 353 breast cancer patients and compared the prognoses after applying the following different definitions of pCR: ypT0/is, ypT0, ypT0/is ypN0, and ypT0 ypN0. Results: pCR was significantly associated with improved distant disease-free survival (DDFS) regardless of the definition (ypT0/is, p = .002; ypT0, p = .008; ypT0/is ypN0, p < .001; ypT0 ypN0, p = .003). Presence of tumor deposits of any size in the lymph nodes (LNs; ypN ≥ 0(i+)) was associated with worse DDFS (ypT0 ypN0 vs ypT0 ypN ≥ 0(i+), p = .036 and ypT0/is ypN0 vs ypT0/is ypN ≥ 0(i+), p = .015), and presence of isolated tumor cells was associated with decreased overall survival (OS; ypT0/is ypN0 vs ypT0/is ypN0(i+), p = .013). Residual ductal carcinoma in situ regardless of LN status showed no significant difference in DDFS or OS (DDFS: ypT0 vs ypTis, p = .373 and ypT0 ypN0 vs ypTis ypN0, p = .462; OS: ypT0 vs ypTis, p = .441 and ypT0 ypN0 vs ypTis ypN0, p = .758). In subsequent analysis using ypT0/is ypN0, pCR was associated with improved DDFS and OS in triple-negative tumors (p < .001 and p = .003, respectively). Conclusions: Based on our study results, the prognosis and rate of pCR differ according to the definition of pCR and ypT0/is ypN0 might be considered a more preferable definition of pCR.

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